RESUMEN
The COVID-19 outbreak can be seen as a 'big test' for China; a summative assessment of its preparedness on multiple fronts, including medical education. Being intimately involved in the coordinated response, the First Affiliated Hospital of Sun Yat-sen University has been a first-hand witness to the strengths and weaknesses of the current medical education system in China. On the one hand, we believe that the distinguished contributions in disease containment efforts by healthcare professionals indicated that our medical education system has achieved its intended outcomes and is socially accountable. On the other hand, we have also identified three major issues that need to be addressed from an educational standpoint: insufficient emphasis on public health emergency preparedness; unsophisticated mechanisms for interdisciplinary cooperation; and inadequate guidance in medical ethics. Whilst these reflections might be seen in its summative form, we would suggest changing it to that of a formative process, where we learn from our assessment through observation and feedback of the gaps, upon which improvement of our present situation can be made. We hope that these lessons may be helpful to our colleagues in the rest of China and around the world, who are engaged in medical educational reform.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Educación Médica/organización & administración , Neumonía Viral/epidemiología , Betacoronavirus , COVID-19 , China/epidemiología , Control de Enfermedades Transmisibles/organización & administración , Planificación en Desastres/organización & administración , Educación Médica/normas , Ética Médica , Humanos , Relaciones Interprofesionales , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: Cardiovascular (CV) safety of one anti-diabetic medication over another remains partially delineated. We sought to assess the comparative effect on CV outcomes among novel anti-diabetic agents. METHODS: This study was registered with the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and Cochrane Library Central Register of Controlled Trials were searched between Jan 1, 1980, and June 30, 2016. Randomized controlled trials comparing anti-diabetic drugs with other comparators in adults with type 2 diabetes were included. We used network meta-analysis to obtain estimates for the outcomes of interests. In addition, post hoc correlation analysis of severe hypoglycemia and primary outcome as per ranking order was conducted. Outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS: A total of 170 trials (166,371 participants) were included. By class and by individual, sulfonylureas (SU) ranked last. Therefore, with SU as reference, categorically sodium-glucose co-transporter 2 inhibitor (SGLT2i), insulin (INS), glucagon-like peptide-1 receptor agonist, and dipeptidyl peptidase 4 inhibitor were significantly superior in term of MACE; as were SGLT2i and INS in term of all-cause mortality. Moreover, ranking orders of MACE and all-cause mortality were both positively correlated with that of severe hypoglycemia risk (by individual: R2 = 0.3178, P = 0.018; by class: R2 = 0.2574, P = 0.038). CONCLUSIONS: Novel anti-diabetic agents possess favorable CV safety profile, despite small but robust differences between individuals. In addition, increase in CV risk was again shown to be partly attributable to a concomitant increase in the risk of severe hypoglycemia, for which SU performed the worst.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/mortalidad , Hipoglucemiantes/efectos adversos , Factores Protectores , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
AIM: To investigate the effects of bezafibrate on the proliferation and differentiation of osteoblastic MC3T3-E1 cells, and to determine the signaling pathway underlying the effects. METHODS: MC3T3-E1 cells, a mouse osteoblastic cell line, were used. Cell viability and proliferation were examined using MTT assay and colorimetric BrdU incorporation assay, respectively. NO production was evaluated using the Griess reagent. The mRNA expression of ALP, collagen I, osteocalcin, BMP-2, and Runx-2 was measured using real-time PCR. Western blot analysis was used to detect the expression of AMPK and eNOS proteins. RESULTS: Bezafibrate increased the viability and proliferation of MC3T3-E1 cells in a dose- and time-dependent manner. Bezafibrate (100 µmol/L) significantly enhanced osteoblastic mineralization and expression of the differentiation markers ALP, collagen I and osteocalcin. Bezafibrate (100 µmol/L) increased phosphorylation of AMPK and eNOS, which led to an increase of NO production by 4.08-fold, and upregulating BMP-2 and Runx-2 mRNA expression. These effects could be blocked by AMPK inhibitor compound C (5 µmol/L), or the PPARß inhibitor GSK0660 (0.5 µmol/L), but not by the PPARα inhibitor MK886 (10 µmol/L). Furthermore, GSK0660, compound C, or N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 1 mmol/L) could reverse the stimulatory effects of bezafibrate (100 µmol/L) on osteoblast proliferation and differentiation, whereas MK886 only inhibited bezafibrate-induced osteoblast proliferation. CONCLUSION: Bezafibrate stimulates proliferation and differentiation of MC3T3-E1 cells, mainly via a PPARß-dependent mechanism. The drug might be beneficial for osteoporosis by promoting bone formation.
Asunto(s)
Bezafibrato/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Células 3T3 , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Bezafibrato/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Osteoblastos/metabolismo , PPAR-beta/metabolismo , Fosforilación/efectos de los fármacos , Factores de TiempoRESUMEN
OBJECTIVE: A previously reported female diagnosed with type A insulin resistance syndrome bearing a heterozygous missense mutation of R1174W in the insulin receptor gene was followed for 7 years since the age of 16 years. METHODS: Five-hour oral glucose tolerance tests (OGTT) were done on baseline, the 3(rd), 6(th) and 7(th) year respectively, with serum insulin and C-peptide measured at the same time points. Areas under of curve (AUC) of glucose, insulin and C-peptide were compared between the years. Acute insulin response (AIR) was determined at baseline and the 7(th) year. The dose response were insulin secretion rates at each time point during OGTT being plotted over the corresponding glucose levels, and the slopes of which quantified the insulin secretion responding to glucose. RESULTS: The follow up data showed that the glucose metabolism of the subject did not deteriorate over time with yearly glycosylated hemoglobin A1c (HbA1c) being normal (4.6% - 5.5%), and hyperinsulinemic hypoglycemia was a persistent phenomenon observed at 4 - 5 hours post-load. The fasting and AUCs of serum insulin and C-peptide tended to decline without simultaneously increase of those of plasma glucose. The AIR decreased by 56% as compared to baseline. The dose response curves shifted downward as years went by. CONCLUSIONS: It supports that with the alleviation of physiological insulin resistance after puberty, the gross hyperinsulinemia tends to ameliorate, and ß-cell secretion does not deteriorate over time as glucose homeostasis maintains.
Asunto(s)
Hiperinsulinismo/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Receptor de Insulina/metabolismo , Adolescente , Glucemia , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina/genética , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Pubertad , Adulto JovenRESUMEN
OBJECTIVE: To investigate the effects of FFA(free fatty acid)on the expression of PANDER (pancreatic derived factor) in ß-cells and to explore the possible relationship between PANDER and Akt signaling pathway at the anti-apoptotic effects of GLP-1 (glucagon-like peptide-1). METHODS: ß-TC3 cells were cultured in vitro with palmitic acid (PA) of different concentrations and different time courses. The expression of PANDER mRNA was analyzed by realtime quantitative PCR (polymerase chain reaction). ß-TC3 cells were cultured with vehicle, 0.5 mmol/L PA, 0.5mmol/L PA + 10nmol/L GLP-1 and 10nmol/L GLP-1 respectively with or without Akti-1/2, a selective inhibitor of Akt, for 12 hours. The protein levels of PANDER, p-Akt and pro-caspase3 were detected by Western blot. And cell apoptosis was analyzed by Hoechst33258 staining. RESULTS: (1) PA could dose and time dependently increased the expression of PANDER mRNA in ß cells (vs. control, P < 0.05); (2) PA increased the PANDER protein expression [(148 ± 18)% vs control 100%, P < 0.05)]. However, these effects were attenuated by GLP-1 [(70 ± 17)% vs PA group, P < 0.01]; (3) Akt inhibitor-1/2 alleviated the effects of GLP-1 on PA inducing the expression of PANDER. The expression of PANDER increased significantly in PA + GLP-1 + Akti-1/2 group [(249 ± 49)% vs PA + GLP-1 group (110 ± 54)%, P < 0.01], and cell apoptosis increased significantly as well [(37.8 ± 1.5)% vs PA + GLP-1 group (20.1 ± 3.5)%, P < 0.01]. CONCLUSION: PA induces the expression of PANDER and the apoptosis of ß cell while GLP-1 counteracts the above effects through an activation of Akt signaling pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Citocinas/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Células Secretoras de Insulina/metabolismo , Ácido Palmítico/farmacología , Páncreas/metabolismo , Animales , Línea Celular , Células Secretoras de Insulina/citología , Ratones , Páncreas/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: To study the effect of smoking on resting energy expenditure (REE) and the relationships among REE, smoking, inflammation and oxidative stress in patients with diabetic kidney disease. METHODS: A case control study of 31 smokers and 40 non-smokers with early stage of diabetic kidney disease (stage III) were performed to evaluate the chronic effect of smoking on REE. REE/fat free mass (FFM), biomarkers of oxidative stress malondialdehyde (MDA), superoxide dismutase (SOD) and inflammation high-sensitivity C-reactive protein (hs-CRP), adiponectin, TNFα were also measured in these subjects. Data were analyzed by Pearson correlation analysis. RESULTS: Compared with non-smokers, REE/FFM in smokers group was significantly increased by 15.96% (P = 0.001). Pearson analysis showed that smoking was significantly correlated with REE/FFM (t = 0.395, P = 0.001). There were significantly different between smokers and non-smokers in MDA, SOD and hs-CRP (P < 0.05). But no difference between two groups in adiponectin and TNFα (P > 0.05). No significant relationships between REE/FFM and MDA, SOD, hs-CRP, adiponectin, TNFα was found (P > 0.05). CONCLUSION: Chronic smoking can lead to increased REE, arouse oxidative stress and inflammatory in patients with early stage of diabetic kidney disease. However, there is no relationship between increased REE due to smoking and oxidative stress and inflammatory.
Asunto(s)
Metabolismo Basal/efectos de los fármacos , Nefropatías Diabéticas/metabolismo , Fumar/efectos adversos , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Estrés OxidativoRESUMEN
OBJECTIVE: To examine the protective effects of appropriate personal protective equipment for frontline healthcare professionals who provided care for patients with coronavirus disease 2019 (covid-19). DESIGN: Cross sectional study. SETTING: Four hospitals in Wuhan, China. PARTICIPANTS: 420 healthcare professionals (116 doctors and 304 nurses) who were deployed to Wuhan by two affiliated hospitals of Sun Yat-sen University and Nanfang Hospital of Southern Medical University for 6-8 weeks from 24 January to 7 April 2020. These study participants were provided with appropriate personal protective equipment to deliver healthcare to patients admitted to hospital with covid-19 and were involved in aerosol generating procedures. 77 healthcare professionals with no exposure history to covid-19 and 80 patients who had recovered from covid-19 were recruited to verify the accuracy of antibody testing. MAIN OUTCOME MEASURES: Covid-19 related symptoms (fever, cough, and dyspnoea) and evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, defined as a positive test for virus specific nucleic acids in nasopharyngeal swabs, or a positive test for IgM or IgG antibodies in the serum samples. RESULTS: The average age of study participants was 35.8 years and 68.1% (286/420) were women. These study participants worked 4-6 hour shifts for an average of 5.4 days a week; they worked an average of 16.2 hours each week in intensive care units. All 420 study participants had direct contact with patients with covid-19 and performed at least one aerosol generating procedure. During the deployment period in Wuhan, none of the study participants reported covid-19 related symptoms. When the participants returned home, they all tested negative for SARS-CoV-2 specific nucleic acids and IgM or IgG antibodies (95% confidence interval 0.0 to 0.7%). CONCLUSION: Before a safe and effective vaccine becomes available, healthcare professionals remain susceptible to covid-19. Despite being at high risk of exposure, study participants were appropriately protected and did not contract infection or develop protective immunity against SARS-CoV-2. Healthcare systems must give priority to the procurement and distribution of personal protective equipment, and provide adequate training to healthcare professionals in its use.
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Infecciones por Coronavirus/prevención & control , Personal de Salud , Control de Infecciones/instrumentación , Pandemias/prevención & control , Equipo de Protección Personal/provisión & distribución , Neumonía Viral/prevención & control , Adulto , Betacoronavirus , COVID-19 , China , Infecciones por Coronavirus/diagnóstico , Estudios Transversales , Femenino , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Exposición Profesional/prevención & control , Neumonía Viral/diagnóstico , SARS-CoV-2RESUMEN
There has been increasing interest in the psycho-socio-relational and sexual disorders of infertility, as the risk of psychological burden among infertile men with sexual dysfunctions is significant. The purpose of this study was to develop and to validate a predictive model to estimate individual psychological burden among infertile men with sexual dysfunction and study the association between them. Comprehensive data were collected for infertile men (n = 480) who sought treatment for infertility in a reproductive medicine center between June 2012 and December 2013. Using independent predictors of psychological burden from the least absolute shrinkage and selection operator, univariable and multivariable analyses were developed into two models. Predictive accuracy was compared between the models. We explored the association between sexual dysfunction and psychological burden. A total of 480 patients were analyzed using 10-fold cross-validation. Independent predictors of psychological burden were incorporated into a model to measure anxiety (corrected-area under curve (AUC): 77.3%) and a model to measure depression (corrected-AUC: 70.2%). Anxiety and depression were both associated with erectile dysfunction (P < 0.05), with anxiety demonstrating the strongest association. Only anxiety was associated with premature ejaculation (P < 0.05). Premature ejaculation was not found to be associated with depression (P > 0.05). Predictive models for psychological burden among infertile men with sexual dysfunction are presented, and we found that there is an association between psychological burden and sexual dysfunction. According to the models, proper counseling and treatment of sexual dysfunction in infertile men may reduce the psychological burden, help attain natural pregnancy, and improve the quality of life.
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Ansiedad/psicología , Depresión/psicología , Infertilidad Masculina/psicología , Calidad de Vida/psicología , Adolescente , Adulto , Estudios Transversales , Disfunción Eréctil/psicología , Humanos , Masculino , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) are at higher risk of future development of diabetes. This study investigated the risk factors associated with early postpartum abnormal glucose regulation (AGR) among Chinese women with a history of GDM. METHODS: A total of 186 women with a history of GDM were screened for early postpartum AGR at 6-8 weeks after delivery. Those with AGR were given lifestyle intervention therapy and reevaluated in 6-12 months. The demographic, anthropometric, prenatal and delivery data were recorded. The plasma high-sensitivity C-reactive protein (HsCRP) and lipid concentration were measured, and insulin secretion were analyzed. Insulinogenic index Deltains30'/DeltaBG30', the homeostasis model assessment index (HOMA)-B, and HOMA-IR were calculated. Multiple regression analysis was performed to identify the risk factors. RESULTS: Of the GDM women 28.0% (52/186) had AGR at 6-8 weeks after delivery; 45.2% (17/40) of these AGR women reminded abnormal after 6-12 month lifestyle intervention. Compared to the women who reverted to normal, women with consistent AGR showed significantly lower fasting insulin concentration, lower Deltains30'/DeltaBG30' as well as lower HOMA-B. No significant differences in age, body mass index (BMI), waist circumference, blood pressure, lipid level, HsCRP and HOMA-IR were observed between the two groups. Pre-pregnancy BMI = 25 kg/m(2), fasting glucose level = 5.6 mmol/L and/or 75 g oral glucose tolerance test (OGTT) 2 hours glucose level = 11.1 mmol/L during pregnancy were predictors for the AGR at 6-8 weeks after delivery. Deltains30'/DeltaBG30 = 1.05 was a significant risk contributor to the consistent early postpartum AGR. CONCLUSION: There is a high incidence of early postpartum AGR among Chinese woman with prior GDM. Beta-cell dysfunction, rather than insulin resistance or inflammation, is the predominant contributor to the early onset and consistent AGR after delivery.
Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Diabetes Gestacional , Células Secretoras de Insulina/fisiología , Trastornos Puerperales/etiología , Adulto , Pueblo Asiatico , China , Femenino , Humanos , Embarazo , Factores de RiesgoRESUMEN
OBJECTIVE: To analyzed the role of genetic factors in pathogenesis of acute intermittent porphyria (AIP). METHODS: Peripheral blood sample was collected from a Chinese female AIP patients, aged 36, to undergo direct sequencing to analyze all the exons and flanking introns of the porphobilinogen deaminase (PBGD) and protoporphyrinogen oxidase (PPOX) genes. The sequencing results were compared with the established human PBGD and PPOX sequences (GenBank Accession No. M95623; NC_000001.9). RESULTS: Direct sequencing showed three kinds of single nucleotide polymorphism (SNP) in the PBGD gene. No mutation was found in the coding regions of either PBGD or PPOX gene. CONCLUSION: The three SNPs may underlie the genetic defects of AIP in Chinese. SNP may serve as genetic markers for linkage analysis to track presymptomatic carriers in AIP families.
Asunto(s)
Pueblo Asiatico/genética , Hidroximetilbilano Sintasa/genética , Polimorfismo de Nucleótido Simple , Porfiria Intermitente Aguda/genética , Adulto , Secuencia de Bases , Exones , Femenino , Humanos , Intrones , Datos de Secuencia MolecularRESUMEN
Liraglutide is administered as glucagon-like peptide-1 (GLP-1) receptor agonist for diabetic patients and can protect pancreatic ß-cells by inhibiting their apoptosis. MicroRNA-139-5p (miRNA-139-5p) participates in the regulation of cancer cell apoptosis. However, it is not clear whether miR-139-5p contributes to the anti-apoptotic effect of liraglutide in ß-cells. The objective of the present study was to investigate the role of miR-139-5p on apoptosis of pancreatic ß-cells. MicroRNA levels in pancreatic tissue from diabetic rats and INS-1 cells treated with liraglutide were measured by real-time quantitative RT-PCR. The role of miR-139-5p on apoptosis was studied by transfecting INS-1 cells with miR-139-5p mimics. The mRNA and protein expression of the target gene, insulin receptor substrate-1 (IRS1), were measured by qRT-PCR and Western blot, respectively. Apoptosis in rat pancreatic tissue and INS-1 cells was detected by TUNEL and annexin V/propidium iodide costaining. Apoptosis of pancreatic tissue from diabetic rats and INS-1 cells was decreased by administration of liraglutide. The expression of miR-139-5p increased in the pancreas of diabetic rats and decreased with liraglutide treatment. Incubation with liraglutide (100 nM) for 48 h attenuated the expression of miR-139-5p and increased the mRNA and protein levels of IRS1. Direct regulatory effects of miR-139-5p on IRS1 were found by a dual-luciferase reporter assay. Transfection of INS-1 cells with miR-139-5p mimics led to decreases in the mRNA and protein expression of IRS1. In conclusion, our observations suggest that decreased miR-139-5p expression contributes to the anti-apoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1.
Asunto(s)
Diabetes Mellitus Experimental/terapia , Hipoglucemiantes/uso terapéutico , Proteínas Sustrato del Receptor de Insulina/genética , Liraglutida/uso terapéutico , MicroARNs/genética , Tratamiento con ARN de Interferencia , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Regulación hacia Abajo , Terapia Genética , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Tratamiento con ARN de Interferencia/métodos , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events. OBJECTIVES: This study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause. METHODS: We performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. RESULTS: Thirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses. CONCLUSIONS: Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.
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Antibacterianos/efectos adversos , Muerte Súbita Cardíaca/etiología , Macrólidos/efectos adversos , Taquicardia Ventricular/etiología , Causas de Muerte , Muerte Súbita Cardíaca/epidemiología , Femenino , Humanos , Masculino , Factores de Riesgo , Taquicardia Ventricular/epidemiologíaRESUMEN
Adrenocorticotrophic hormone (ACTH)-producing pituitary adenoma leads to excess ACTH secretion, which is associated with significant mortality and impaired quality of life. Thus far, the first line therapy is the transphenoidal microsurgery. Considering the high recurrence rate and complications of surgery, novel agents, which directly target on pituitary ACTH-producing adenoma and suppress ACTH secretion are urgently required. In the present study, the effect of ursolic acid (UA) as a candidate agent targeting ACTH-producing AtT20 cells was investigated. It was demonstrated that UA inhibited the viability and induced apoptosis of AtT20 cells and decreased ACTH secretion. The process of apoptosis involved a decrease of the B cell lymphoma 2 (Bcl-2)/Bcl2-associated X protein ratio followed by a release of mitochondrial cytochrome c into the cytosol with subsequent activation of caspase-9, -3/7 and -8. The potential signaling pathway involved the activation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinases1/2 and p38 mitogen-activated protein kinase. The JNK pathway participated in UA-induced mitochondrial apoptotic signaling transduction via increasing the phosphorylation and degradation of Bcl-2, which may be partly attenuated by the JNK inhibitor SP600125. In conclusion, the present study indicates that UA may be a promising candidate agent for the management of ACTH-producing pituitary adenoma.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Antineoplásicos Fitogénicos/farmacología , Triterpenos/farmacología , Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma Hipofisario Secretor de ACTH/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ácido UrsólicoRESUMEN
High-fat diet (HFD) is an environmental factor that contributes to the pathogenesis of obesity and type 2 diabetes. A number of genes influencing oxidative phosphorylation (OXPHOS) were found to be downregulated in skeletal muscle of humans and rats treated with HFD and have been implicated in mitochondrial dysfunction, insulin resistance, and consequent type 2 diabetes. In this study, we hypothesized that DNA methylation plays a crucial role in the regulation of OXPHOS genes in skeletal muscle of rats exposed to HFD. Using whole genome promoter methylation analysis of skeletal muscle followed by qPCR and bisulfite sequencing analysis, we identified hypermethylation of Cox5a in HFD rats. Furthermore, we found that Cox5a hypermethylation was associated with downregulation of Cox5a expression at the mRNA and protein level, and a reduction in mitochondrial complex IV activity and ATP content in HFD-induced insulin resistant rats compared to controls. Moreover, we found that while exposure to palmitate resulted in hypermethylation of the Cox5a promoter in rat myotubes, demethylation with 5-aza-2'-deoxycytidine was associated with preserved Cox5a expression, as well as restoration of complex IV activity and cellular ATP content. These novel observations indicate that Cox5a hypermethylation is associated with mitochondrial dysfunction in skeletal muscle of HFD-induced insulin resistant rats.
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Metilación de ADN , Dieta Alta en Grasa/efectos adversos , Complejo IV de Transporte de Electrones/genética , Resistencia a la Insulina/genética , Mitocondrias Musculares/genética , Obesidad/genética , Animales , Células Cultivadas , Regulación hacia Abajo , Complejo IV de Transporte de Electrones/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/inducido químicamente , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación Oxidativa/efectos de los fármacos , Regiones Promotoras Genéticas , Ratas , Ratas Wistar , Análisis de Secuencia de ADNRESUMEN
AIM: To investigate the perinatal complications and risk of thyroid dysfunction at early childhood of Graves' disease (GD) mothers with euthyroidism (EU) or subclinical hyperthyroidism (sHT) during pregnancy. METHOD: One hundred and twenty-three pregnant women with GD were recruited. They were all in euthyroidism with treatment of anti-thyroid drugs (ATDs) before pregnancy. All the pregnant GD women maintained EU (n=55) or sHT (n=68) by using ATDs. Sixty randomly selected, age-matched healthy pregnant women (non-GD control) were included. The prenatal and newborn data were collected and analyzed. Toddlers of GD mothers (n=45) and non-GD healthy mothers (n=36) were also recruited for thyroid function and growth assessments. RESULTS: Newborns of mothers with GD had significantly higher complications than those of non-GD mothers. The percent of perinatal complications were 5.0%, 30.9% and 32.3% in the control, EU (vs. control, p<0.001), and sHT (vs. control, p<0.001) groups, respectively. There were no differences between the women continuing low doses of ATDs at the start of pregnancy and the women who stopped receiving ATDs at the start of pregnancy. Toddlers' serum levels of FT3, FT4, anti-thyroglobulin antibody, and anti-thyroid peroxidase antibody were significantly higher than those of non-GD mothers (all p<0.05). CONCLUSION: Pregnancy with GD significantly increases the perinatal complications even with EU. The continued use of ATDs at the start of pregnancy does not give an increased risk of perinatal complications in GD mothers. Maternal GD may also induce a higher risk of autoimmue thyroid dysfunction among offspring at early childhood.
Asunto(s)
Enfermedad de Graves/fisiopatología , Complicaciones del Embarazo/fisiopatología , Pruebas de Función de la Tiroides , Adulto , Niño , Femenino , Enfermedad de Graves/complicaciones , Humanos , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND: Pancreatic beta-cell apoptosis induced by lipotoxicity, to a large extent, contributes to the progression of type 2 diabetes. To investigate the mechanism of free fatty acid induced apoptosis, we aimed to study the effects of palmitic acid (PA) on the apoptosis and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in ßTC3 cells as well as the possible role of nuclear factor-κB (NF-κB) in this process. METHODS: Hoechst 33258 was used to detect ßTC3 cell apoptosis, which was induced by PA stimulation for 12 hours. PGC-1α expression was analyzed by reverse transcription polymerase chain reaction, IκB kinase ß (IKKß), IκBα, NF-κB-inducing kinase (NIK) and Rel-B expressions were analyzed by Western blotting. MG132 was employed to block the endogenous IκBα degradation before PA administration, and then its effect on PA-inducing cell apoptosis and PGC-1α mRNA expression was analyzed. RESULTS: Significant increased cell apoptosis was found at the concentration of 0.5 mmol/L and 1.0 mmol/L PA administration. PA (0.5 mmol/L) could extensively reduced the expression of PGC-1α mRNA. After exposing ßTC3 cells to 0.5 mmol/L PA for different time periods (0, 4, 6, 8, 10 and 12 hours), IKKß protein expression increased while IκBα, NIK and Rel-B protein expression declined in a time-dependent manner. Pretreatment with MG132 to inhibit the degradation of IκBα, partially prevented the down-regulation of PGC-1α mRNA expression after 12-hour PA treatment in accordance with the decrease of PA induced apoptosis. CONCLUSIONS: NF-κB canonical pathway was activated in PA-mediated ßTC3 cell apoptosis, whereas non-canonical pathway was inhibited. Reduced PGC-1α expression by PA in ßTC3 cells could involve the activation of canonical NF-κB pathway, so as to deteriorate the PA induced apoptosis.
Asunto(s)
Proteínas de Choque Térmico/metabolismo , Células Secretoras de Insulina/metabolismo , FN-kappa B/metabolismo , Ácido Palmítico/farmacología , Factores de Transcripción/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Proteínas de Choque Térmico/genética , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Leupeptinas/farmacología , FN-kappa B/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genéticaRESUMEN
AIM: To assess the prevalence and predictors of post-transplant diabetes mellitus (PTDM) in Chinese renal recipients and describe their long-term evolution of glucose metabolism. METHODS: 887 non-diabetic Chinese adult renal recipients were studied retrospectively, with a median follow-up of 7 years. PTDM patients were categorized into transient PTDM and permanent PTDM. The cumulative incidence and risk factors of PTDM were estimated by Kaplan-Meier and Cox regression. RESULTS: The cumulative incidence of PTDM at 3 months, 1, 3, 5, 10, 15 and 20 years post-transplant was 10.4%, 11.4%, 13.4%, 15.2%, 22.7%, 27.9% and 38.3%, respectively. 61.9% of PTDM cases were diagnosed within the first three months and 61.6% of them developed persistent diabetes in the future. Risk factors for all PTDM included older age, body mass index (BMI)≥25 kg/m(2), triglycerides≥1.5 mmol/L, rejection, the use of tacrolimus and diltiazem. The predictors of permanent PTDM included age >50 years (RR=2.322, 95% CI 1.255-4.296, P=0.007), BMI≥25 kg/m(2) (RR=1.699, 95% CI 1.014-2.846, P=0.044) and the use of tacrolimus (RR=1.835, 95% CI 1.181-2.851, P=0.007). CONCLUSIONS: Patients were most susceptible to PTDM within the first three months post-transplant and more than half of them developed persistent diabetes in the future. Age >50 years, overweight and tacrolimus application were risk factors for both PTDM and permanent PTDM.
Asunto(s)
Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Glucosa/metabolismo , Trasplante de Riñón/efectos adversos , Adulto , Pueblo Asiatico , Diabetes Mellitus/etiología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Insulin resistance is an underlying feature of both type 2 diabetes and metabolic syndrome. Currently, it is unclear whether nuclear factor (NF)-κB inducing kinase (NIK) plays a role in the development of insulin resistance. The present in vivo study investigated the roles of NIK and IκB kinase α (IKKα) in obesity-induced insulin resistance using animal models. METHODS: NIK expression was evaluated by Western blotting in male Lep(ob) mice and C57BL/6J mice fed a high-fat diet (HFD) (45% fat). After metformin and sulfasalazine treatment, NIK expression was investigated during the improvement of insulin resistance. RESULTS: NIK was increased by about 1-fold in the renal tissues of Lep(ob) mice and C57BL/6J mice fed a HFD for 12 weeks. After 1 and 3 weeks of high-fat feeding, we observed an almost 50% decrease in NIK and IKKα expression in the liver and renal tissues of C57BL/6J mice. NIK expression was significantly lower in the liver and renal tissues of HFD-fed mice that were treated with insulin sensitizers, metformin and sulfasalazine. However, IKKα expression was increased after metformin treatment in both tissues. CONCLUSION: These results suggest a possible role of NIK in the liver and renal tissues of insulin-resistant mice.